A computational model for understanding stem cell, trophectoderm and endoderm lineage determination.
BACKGROUND
Recent studies have associated the transcription factors, Oct4, Sox2 and Nanog as parts of a self-regulating network which is responsible for maintaining embryonic stem cell properties: self renewal and pluripotency. In addition, mutual antagonism between two of these and other master regulators have been shown to regulate lineage determination. In particular, an excess of Cdx2 over Oct4 determines the trophectoderm lineage whereas an excess of Gata-6 over Nanog determines differentiation into the endoderm lineage. Also, under/over-expression studies of the master regulator Oct4 have revealed that some self-renewal/pluripotency as well as differentiation genes are expressed in a biphasic manner with respect to the concentration of Oct4.


RESULTS
We construct a dynamical model of a minimalistic network, extracted from ChIP-on-chip and microarray data as well as literature studies. The model is based upon differential equations and makes two plausible assumptions; activation of Gata-6 by Oct4 and repression of Nanog by an Oct4-Gata-6 heterodimer. With these assumptions, the results of simulations successfully describe the biphasic behavior as well as lineage commitment. The model also predicts that reprogramming the network from a differentiated state, in particular the endoderm state, into a stem cell state, is best achieved by over-expressing Nanog, rather than by suppression of differentiation genes such as Gata-6.


CONCLUSIONS
The computational model provides a mechanistic understanding of how different lineages arise from the dynamics of the underlying regulatory network. It provides a framework to explore strategies of reprogramming a cell from a differentiated state to a stem cell state through directed perturbations. Such an approach is highly relevant to regenerative medicine since it allows for a rapid search over the host of possibilities for reprogramming to a stem cell state.
Chickarmane
Vijay
V
Division of Biology, California Institute of Technology, Pasadena, California, United States of America.
Peterson
Carsten
C
D002454:Cell Differentiation; D019070:Cell Lineage; D019295:Computational Biology / Q000379:methods*; D004475:Ectoderm; D004707:Endoderm; D050993:GATA6 Transcription Factor; D053263:Gene Regulatory Networks; D006487:Hemostasis; D018398:Homeodomain Proteins; D006801:Humans; D008954:Models, Biological; D008962:Models, Theoretical; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; D039904:Pluripotent Stem Cells; D055748:SOXB1 Transcription Factors; D013234:Stem Cells / Q000166:cytology*; D014157:Transcription Factors; D014327:Trophoblasts
D050993:GATA6 Transcription Factor; D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors